Usuario:Jaescudero/Taller

Didier Mazel is a French researcher working at Institut Pasteur de Paris. He is the leader of the Bacterial Genome Plasticity Unit.

Introduction editar

He studied biochemistry and genetics at University Pierre et Marie Curie (now Sorbonne Université), and defended his PhD in Molecular and Cellular Genetics in 1990, on the characterization of the genes encoding the light harvesting complexes in cyanobacteria and their regulation by the light spectral composition. In parallel, he demonstrated that the metabolic constraints linked to the availability of elemental sulfur in the different types of water colonized by cyanobacteria, were imprinted in their protein sequences (Nature 1989). He then became interested in the special place of methionine, a sulfur containing amino acid, in translation initiation. He performed a Post doc on the formylation/deformylation steps of the translation initiation process in bacteria and he successfully identified the deformylase (PDF) gene and showed that this essential activity, exclusively found in bacteria, was an ideal target for the development of new antibiotics (EMBO J 1994, J. Mol Biol. 1997). This seminal observation led the development of several PDF inhibitors by the pharmaceutical industry which are now in clinical trials.

In 1996, Didier Mazel moved to the antibiotic resistance field and started working on integrons. At that time, the origin of this genetic system, which was exclusively found associated with the development and spread of multiple antibiotic resistances in Gram-negative pathogens, was unknown. In these elements, the resistance genes are carried in independent mobile units called gene cassettes. Based on phylogenic analyses Mazel hypothesised that the origin of these elements predated the clinical use of antibiotics and that integrons should have a broader role in bacterial adaptation in nature.

Integrons editar

Didier Mazel has since made several important contributions to the study of integrons that allows considering him the leader in the field. He has worked on multiple facets of these platforms, from fundamental mechanistic aspects of recombination, to antibiotic resistance, through their important relationship with bacterial cell physiology. In collaboration with Julian Davies, he discovered the first example of ancestral integron in the genome of Vibrio cholerae(Science 1998). Since, he has shown that these structures, named sedentary chromosomal integrons, are commonly found in the genome of various environmental genera such as Vibrio, Xanthomonas, Pseudomonas, etc (PNAS 2001, Genome Research 2003). Sedentary Chromosomal Integrons can carry hundreds of such cassettes of varied functions and are the most variable part of the genome of these bacteria. Hence, these genetic elements provide an unlimited source of cassettes, dedicated not only to antibiotic resistance but also to a multiplicity of adaptive functions for Gram negative bacteria. Mazel and colleagues have demonstrated that the recruitment of super-integron cassettes can lead to novel resistance phenotypes (Mol Mic 2002). He has made exceptional contributions to the understanding of the fundamental mechanisms of cassette capture, and dissemination of resistance genes. In particular, he has proposed and demonstrated in vivo(EMBO J., 2005) a novel recombination archetype, involving a single-stranded DNA intermediate. This model explained the former paradoxes of the system, and was applicable to other genetic elements involved in HGT, such as the CTX phage (Mol. Cell, 2005). Determination of the crystal structure of the integron integrase in complex with its single strand substrate identified the determinants allowing the system to recombine sites that do not show primary sequence conservation (Nature 2006). The Mazel group has demonstrated how this innovative activity on ss-DNA evolved from a canonical tyrosine-recombinase (Nature Comm. 2016), and has established the physiological conditions under which the recombination substrate is made available (EMBO J., 2010, NAR 2012, mBio 2017,..). His research showed definitively that integron recombination was intimately intertwined with bacterial physiology through the control of integrase expression by the bacterial SOS response (Science, 2009). Although this mechanism directly links DNA damage to integron activity, the Mazel lab recently demonstrated that many antibiotics, that do not target DNA metabolism, induce this major stress response system in bacteria even when present at subinhibitory concentrations. Thus, antibiotics do not only trigger resistance cassette recombination and capture, but also increase the odds of resistance development by point mutations (Antimicrobial Agents and Chemotherapy, 2011; PLoS Genet. 2013, NAR 2014).

Chromosome structure, Horizontal Gene Transfer and biotechnological interests editar

As it is often the case of excelling scientists, Didier Mazel has broad scientific interests that go well beyond the field of integrons. His group also studies genome organization and chromosome maintenance mechanisms in Vibrio cholerae, which, as in all Vibrio species, is constituted of 2 circular chromosomes (chr). Vibrio species are fast growing bacteria, and several are important pathogens for human and/or marine animals. It is very likely that this specific genome partition plays a yet unknown key role in their evolutionary success. His group has addressed these questions undertaking an approach based on the radical remodelling of genomic structure, creating strains with a single chromosome, or with 2 chromosomes of variable size. Using this original approach, they already established several selective advantages conveyed by this organization, and ruled out other previously proposed hypothesis (PLoS Genetics, 2012; Mol. Microbiol, 2014). They recently identified the unique mechanism that coordinates chr2 replication, to ensure synchronous replication termination for the two chromosomes. They found that this is mediated through physical contact between specific regions of the two chromosomes and that it involves replication of a non-coding 150 bp long sequence on chr1 (Science Adv 2016, NAR 2018).

In addition to endogenous sources, ssDNA is systematically associated to the two main mechanisms of lateral gene transfer, conjugation and transformation, and occasionally, to transduction. Most of the genetic elements responsible for the dissemination of antibiotic resistance such as transposons and their embedded integrons, are carried on conjugative plasmids and undergo extensive exchange within bacterial populations (for example, in the human GI tract). The Mazel group has examined if the amount of ssDNA naturally produced during conjugation or transformation induced the SOS response in recipient bacteria. This was indeed the case, and it was found that it was sufficient to trigger cassette recombination, thus illustrating how cassettes could be captured in the mobile integron and disseminated among unrelated bacteria (PLoS Genetics 2010, J. Bacteriol, 2012).

Recently, the Mazel lab delivered a project aiming at developing novel antimicrobial strategies to tackle antibiotic resistance. In this case, killing was based on the use of type II TA toxins and inteins, and they demonstrated that these weapons could be used to kill specifically Vibrio choleraein complex populations such as the microbiota of fishes or crustaceans. By leaving the remaining microbiota unaffected, these tools could be more efficient than classical broad spectrum antibiotics in the clinic and less prone to the development of bacterial resistance (Nat biotech). He has therefore become one of the pioneers in leveraging synthetic biology to invent novel antimicrobials.